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Genome-wide analysis of H3K79 methylation in CD34+ CD19+ cells from normal marrow, MLL-rearranged or MLL-germline ALL

ABSTRACT: We created a mouse model where conditional expression of physiologic levels of an Mll-AF4 fusion oncogene induces development of acute lymphoblastic (ALL) or acute myeloid leukemias (AML). ChIP-chip analysis demonstrated increased histone H3 Lysine 79 (H3K79) dimethylation that correlated with Mll-AF4 associated gene expression profiles in murine ALLs, and in human MLL-rearranged leukemias. In addition, human MLL-rearranged ALLs can be distinguished from other ALLs by their genome-wide H3K79 methylation profiles. Keywords: Cell type comparison

ORGANISM(S): Homo sapiens

PROVIDER: GSE12360 | GEO | 2008/11/04

SECONDARY ACCESSION(S): PRJNA114197

REPOSITORIES: GEO

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Genome-wide analysis of H3K79 dimethylation in MLL-AF4 leukemic bone marrow

Project description:We created a mouse model where conditional expression of physiologic levels of an Mll-AF4 fusion oncogene induces development of acute lymphoblastic (ALL) or acute myeloid leukemias (AML). ChIP-chip analysis demonstrated increased histone H3 Lysine 79 (H3K79) dimethylation that correlated with Mll-AF4 associated gene expression profiles in murine ALLs, and in human MLL-rearranged leukemias. In addition, human MLL-rearranged ALLs can be distinguished from other ALLs by their genome-wide H3K79 methylation profiles. Keywords: Cell type comparison

2008-11-04 | GSE12362 | GEO

Genome-wide analysis of H3K79 dimethylation in normal and MLL-AF4 leukemic pre-B cells

Project description:We created a mouse model where conditional expression of physiologic levels of an Mll-AF4 fusion oncogene induces development of acute lymphoblastic (ALL) or acute myeloid leukemias (AML). ChIP-chip analysis demonstrated increased histone H3 Lysine 79 (H3K79) dimethylation that correlated with Mll-AF4 associated gene expression profiles in murine ALLs, and in human MLL-rearranged leukemias. In addition, human MLL-rearranged ALLs can be distinguished from other ALLs by their genome-wide H3K79 methylation profiles. Keywords: Cell type comparison

2008-11-04 | GSE12361 | GEO

H3K79 methylation profiles define murine and human MLL-AF4 leukemias

2008-11-04 | GSE12363 | GEO

Transcription profiling of mouse normal lymphoid progenitors and MLL-AF4 leukemic lymphoblasts

2008-11-13 | E-GEOD-12310 | biostudies-arrayexpress

Expression profiling of normal murine lymphoid progenitors and MLL-AF4 leukemic lymphoblasts

2008-11-04 | GSE12310 | GEO

Transcription profiling of mouse activated or control 5-FU bone marrow from MLL-AF4stop knockins

Project description:We created a mouse model where conditional expression of physiologic levels of an Mll-AF4 fusion oncogene induces development of acute lymphoblastic (ALL) or acute myeloid leukemias (AML). Immunophenotypic and gene expression analysis of the ALL cells demonstrated bone marrow replacement with B-precursor cells which express a gene expression profile that has significant overlap with profiles in human MLL-rearranged ALL. To examine early, pre-leukemic changes in lymphoid cells due to Mll-AF4 expression, we infected 5-FU bone marrow cells from Mll-AF4stop knocking mice with activating (Cre-GFP) or control (MIF-GFP) retrovirus ex vivo and measured expression changes after culture under lymphoid growth conditions. Experiment Overall Design: Mll-AF4stop knock-in mice were treated with 5-FU and 5 days later their bone marrow infected ex vivo with either Cre-GFP to activate the Mll-AF4 fusion construct or with a control MIG-Cre retrovirus. GFP+ cells were sorted 2 days post-infection and cultured for 14 days under lymphoid growth conditions before total RNA was isolated for hybridization to Affymetrix expression microarrays.

2008-11-13 | E-GEOD-12313 | biostudies-arrayexpress

Expression profiling of activated or control 5-FU bone marrow from MLL-AF4stop knockin mice

2008-11-04 | GSE12313 | GEO

The MLL-AF9 and MLL-AF4 oncofusion proteins bind a distinct enhancer repertoire and target the RUNX1 program in MLLr AML

Project description:In MLL-rearranged (MLLr) leukemias the N terminal part of the MLL gene can be fused to over 60 different partner genes. Here, we investigate the genome wide binding of the MLL-AF9 and MLL-AF4 fusion proteins and their epigenetic signatures in order to define a core set of MLLr targets. We uncover both common as well as specific MLL-AF9 and MLL-AF4 target genes, which are all marked by H3K79me2, H3K27ac, and H3K4me3. Apart from promoter binding, we also identify MLL-AF9 and MLL-AF4 binding at specific subsets of non overlapping active distal regulatory elements. Despite this differential enhancer binding MLL-AF9 and MLL-AF4 still share a common gene program, which represents part of the RUNX1 gene program and constitutes of CD34+ and monocyte specific genes. Comparing these datasets revealed several zinc finger transcription factors as potential MLL-AF9 co-regulators. Together these results suggest that MLL-fusions collaborate with specific subsets of TFs to aberrantly regulate the RUNX1 gene program in 11q23 AMLs.

2017-01-24 | GSE79899 | GEO

MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia.

Project description:Understanding the underlying molecular mechanisms of defined cancers is crucial for effective personalized therapies. Translocations of the Mixed Lineage Leukemia (MLL) gene produce fusion proteins such as MLL-AF4 that disrupt epigenetic pathways and cause poor prognosis leukemias. Here we find that MLL-AF4 occupies a subset of unmethylated CG-enriched genes in combination with its cofactors Menin/LEDGF and ENL. MLL-AF4 mainly displays a punctate binding pattern near gene promoters, but we also observe a second less common pattern where MLL-AF4 spreads into the gene body and is associated with increased transcription and increased histone H3 lysine 79 methylation (H3K79me2/3). Compared to other H3K79me2/3 marked genes, MLL-AF4 spreading genes are more sensitive to inhibitors of the H3K79 methyltransferase DOT1L. This sensitivity mediates synergistic interactions with additional targeted drug treatments. Therefore, epigenetic spreading and enhanced susceptibility to epidrugs provides a potential new Achilles heel for guiding combination therapies in humans.

2017-01-12 | GSE83671 | GEO

The histone H2B ubiquitin ligase RNF20 is required for MLL-rearranged leukemia

Project description:MLL-fusions are potent oncogenes that initiate aggressive forms of acute leukemia. As aberrant transcriptional regulators, MLL-fusion proteins alter gene expression in hematopoietic cells through interactions with the histone H3 lysine 79 (H3K79) methyltransferase DOT1L. Notably, interference with MLL-fusion cofactors like DOT1L is an emerging therapeutic strategy in this disease. Here we identify the histone H2B E3 ubiquitin ligase RNF20 as an additional requirement for MLL-fusion-mediated leukemogenesis. Suppressing the expression of Rnf20 in diverse models of MLL-rearranged leukemia leads to inhibition of cell proliferation; under tissue culture conditions as well as in vivo. Rnf20 knockdown leads to reduced expression of MLL-fusion target genes, including Hoxa9 and Meis1; effects that resemble Dot1l-inhibition. Using ChIP-seq, we found that H2B ubiquitination (H2Bub) is enriched in the body of MLL-fusion target genes, correlating with sites of H3K79 methylation and transcription elongation. Furthermore, we found that Rnf20 is required to maintain local levels of H3K79 di-methylation by Dot1l at Hoxa9 and Meis1. These findings support a model whereby co-transcriptional recruitment of Rnf20 at MLL-fusion target genes leads to amplification of Dot1l-mediated H3K79 methylation, thereby rendering leukemia cells dependent on Rnf20 to maintain their oncogenic transcriptional program. Examination of gene expression profiles upon RNF20 RNAi in MLL-AF9 acute myeloid leukemia cells

2013-02-19 | E-GEOD-43725 | biostudies-arrayexpress

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